Discovery of gramicidin A analogues with altered activities by multidimensional screening of a one-bead-one-compound library.

ABSTRACT: Gramicidin A (1) is a peptide antibiotic that disrupts the transmembrane ion concentration gradient by forming an ion channel in a lipid bilayer. Although long used clinically, it is limited to topical application because of its strong hemolytic activity and mammalian cytotoxicity, likely arising from the common ion transport mechanism. Here we report an integrated high-throughput strategy for discovering analogues of 1 with altered biological activity profiles. The 4096 analogue structures are designed to maintain the charge-neutral, hydrophobic, and channel forming properties of 1. Synthesis of the analogues, tandem mass spectrometry sequencing, and 3 microscale screenings enable us to identify 10 representative analogues. Re-synthesis and detailed functional evaluations find that all 10

SUBMITTER: Takada Y 

PROVIDER: S-EPMC7531004 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature